Demethylation of 14-hydroxy substituted alkaloid derivatives

ABSTRACT

The present invention is directed to a method for demethylating 14-hydroxy substituted alkaloid derivatives, in particular of 14-hydroxy-17-methyl-4,5-epoxymorphinane-6-on-derivatives. This is achieved by reacting a starting compound with a compound of general formula R 1 OOC—N═N—COOR 2  in a suitable solvent.

The present invention is directed to a method for demethylating14-hydroxy substituted alkaloid derivatives, in particular of14-hydroxy-17-methyl-4,5-epoxymorphinane-6-on-derivatives. This isachieved by reacting a starting compound with a compound of generalformula R¹OOC—N═N—COOR² in a suitable solvent.

BACKGROUND OF THE INVENTION

Naltrexone is an opioid receptor antagonist used primarily in themanagement of alcohol dependence and opioid dependence. It is availableon the market in form of its hydrochloric salt, i.e. naltrexonehydrochloride. Naltrexone and its active metabolite 6β-naltrexol arecompetitive antagonists at μ- and κ-opioid receptors, and to a lesserextent at δ-opioid receptors. The plasma halflife of naltrexone is about4 hours, for 6-β-naltrexol 13 hours.

One important step in the synthesis of naltrexone is a demethylationstep for removing the methyl group from the nitrogen atom of thealkaloid molecule, as it is present for example in oxycodone andoxymorphone.

One way to achieve this demethylation step is disclosed in GB-1,124,441.Therein, a process of removing a methyl group from a tertiary nitrogenatom of an alkaloid molecule is disclosed, comprising reacting themethylated compound with a lower alkyl azodicarboxylate, wherein thelower alkyl group has from 1-8 carbon atoms, for a time sufficient tobring about a reaction and to provide a demethylated alkaloidderivative. However, the patent specification is only related toalkaloid compounds, which do not carry an OH-group at C14 of thealkaloid backbone. For example, GB-1,124,441 is silent on how to performa demethylation on oxycodone and oxymorphone, respectively.

The paper titled “Reactions of Azodicarboxylic Esters with Amines” of S.HOSZTAFI, Österreichische Apotheker-Verlagsges.m.b.H., Wien, 1987,describes the reactions of aliphatic and aromatic amines and alkaloidswith azodicarboxylic esters.

Further documents are available which are related to the demethylationof alkaloids, for example, EP 0 295 783 discloses diethylazodicarboxylate for demethylating alkaloids. On page 8 of thedescription, it is disclosed to use diethyl azodicarboxylate inacetonitrile for the N-dealkylation of a compound of the indicatedformula. However, in the course of this reaction, a bridging group isintroduced between 2N-atoms as it can be seen from formula (VII).Furthermore, EP 0 295 783 is not related to alkaloids having a 14-OHgroup.

The like, GB-1,179,479 discloses removing a methyl group by treatmentwith a di-lower alkyl azodicarboxylate, wherein the lower alkyl grouphas from 1-4 carbon atoms, followed by treatment of delute mineral acid.This reaction, however, is disclosed in the context of general formula(I) as indicated in GB-1,179,479, which does not possess a 14-OH group.

In the prior art, there are also chemical processes disclosed, whichallow the demethylation of alkaloid compounds which are carrying anOH-group at C14. In these methods, however, the OH group is beingprotected in order to avoid a reaction with the usual demethylationagents.

For example, oxycodone may be reacted with Ac₂O in order to achieveacetyloxycodone (having a protected OH-group) which is further convertedby well-known demethylating agents (BrCN/H₂SO₄) to noroxycodone (whichis demethylated).

The same step can be performed in the synthesis of noroxymorphone,starting from oxymorphone. There, oxymorphone is reacted with Ac₂Oresulting in a protected OH-group at C14 (oxymorphone diacetate). Afterreacting with BrCN and H₂SO₄, noroxymorphone is yielded. The conversionby means of BrCN is described in IIJIMA et al., “Studies in the(+)-Morphinan Series. 5. Synthesis and Biological Properties of(+)-Naloxone”, Journal of Medicinal Chemistry, 1978, Vol. 21, No. 4.

However, there is not any disclosure in the art for a process fordemethylating alkaloid derivatives which are carrying the 14-OH group,which 14-OH group is not being protected during the reaction. This mightbe due to the fact that conventional demethylating agents, such as BrCN,do not function under these circumstances as proper demethylatingagents: The free OH group at C14 is too close to the cyanide and canperform a 5-exo-dig-cyclization which would not allow a properperformance of the reaction. See in this connection, CURRIE, A. C.;NEWBOLD, G. T. et al., Roy. Coll. Sci., Technol., Glasgow, UK, Journalof the Chemical Society, abstracts (1961), 4693-4700.

Further, see also GB-975,601, published in 1964. Here, it is disclosedthat 14-acetoxy-N-cyanonorcodeine acetate may be produced by reacting14-acetoxycodeine acetate with cyanogen bromide and may be converted to14-hydroxynorcodeine by means of lithium aluminium hydride.

SUMMARY OF THE INVENTION

Therefore, there is a need remaining to provide a method ofdemethylating 14-OH substituted alkaloid derivatives, and in particular,oxycodone and oxymorphone without the need of protecting/deprotectingthe 14-OH group. Furthermore, it is an object of the present inventionto provide a method of demethylating alkaloid derivatives which isenvironment-friendly and allows a conversion of 14-OH-alkaloidderivatives to the respective nor-alkaloid-derivatives in a high yield.

These problems are solved by the subject-matter of the independentclaim. Embodiments are set forth in the dependent claims.

By the present invention, for the first time, a way of demethylatingalkaloid derivatives having a 14-OH group is provided without the needof protecting the OH group during the reaction. This, surprisingly,could be achieved by using azodicarboxylic acid dialkyl esters ofgeneral formula R¹OOC—N═N—COOR² in a suitable solvent. This is insofarsurprising as the prior art teaches that the 14-OH group is too reactivefor using the conventional demethylating agents as discussed abovewithout having protected the 14-OH group before.

By the new process of demethylation, two additional steps can beavoided, i.e. protecting and deprotecting the 14-OH-group of thealkaloid derivative. Furthermore, by using azodicarboxylic acid dialkylester compounds as, for example, DIAD or DEAD, substances, which arepotentially harmful to the environment (like BrCN) may be avoided.

In order to give an overview over the improvements achieved by thepresent invention, it is referred to the enclosed FIGS. 1 and 2 showingtwo conventional ways for the synthesis of naltrexone base. Here,oxycodone is converted to acetyloxycodone in order to provide aprotective group for 14 OH, and, then, demethylation is achieved bymeans of BrCN in order to achieve noroxycodone or noroxymorphone,respectively.

FIG. 3 describes the reaction of the present invention. Here, oxycodoneis converted directly to noroxycodone, as it is also the case foroxymorphone to noroxymorphone (see FIG. 4).

It could be shown by the inventors that the yield of this reaction stepis quite high, for example, for the conversion of oxymorphone tonoroxymorphone the yield is about 80-90%.

DETAILED DESCRIPTION OF THE INVENTION

In particular, the present invention is directed to the following:

According to a first aspect, the invention is directed to a method ofproducing a compound of formula (I)

or a salt thereof, comprisingreacting a compound of formula (II)

with an azodicarboxylic acid dialkyl ester of general formulaR¹OOC—N═N—COOR² in a suitable solvent whereinX is selected from H, alkyl, silyl or acetyl;R¹ and R² are independently selected from linear or branched substitutedor unsubstituted alkyl, preferably C₁-C₆-alkyl, more preferably methyl,ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl,hexyl, benzyl, piperidyl; andwherein the bond between atoms 7 and 8 is a single or a double bond,in order to obtain the compound of formula (I).

Salts of the above compound of formula (I) include carboxylate salts andothers that are within a reasonable benefit/risk ratio,pharmacologically effective and suitable for contact with the tissues ofpatients without undue toxicity, irritation, or allergic response.Representative salts include hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate,stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, naphthylale, mesylate,glucoheptonate, lactiobionate, and laurylsulfonate. See for example, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., J. 977,66:1-19, which is incorporated herein by reference.

The hydrochloride salt is preferred.

The azodicarboxylic acid dialkyl ester of formula R¹OOC—N═N—COOR²preferably is selected from compounds, wherein R¹ and R² are each ethylor isopropyl, respectively, termed diethyl azodicarboxylate (DEAD) anddiisopropyl azodicarboxylate (DIAD), or mixtures thereof.

In the reaction mixture, these compounds preferably are used in anamount of 1.5 to 3.0 eq.

In a further embodiment, the solvent is an aprotic polar or dipolarsolvent and is preferably selected from methanol, ethanol, acetone,toluene, dimethylformamide, N,N-dimethylacetamide, acetonitrile, aceticacid ethylester and methyl-tert-butylether. Other solvents which fallinto this category are methylene chloride, chloroform, tetrahydrofuran,dioxane, 1,3-dimethyl-2-imidazolidinone, dimethylsulfoxide, nitromethaneor hexamethylphosphoric triamide. The starting material may becompletely or partly dissolved within the aprotic polar or dipolarsolvent.

The most preferred solvent is dimethylformamide.

The above demethylation reaction from a compound of formula (II) to acompound of formula (I) preferably is performed at a temperature in therange of room temperature (20° C.) to 100° C., preferably in the rangeof from 30-90° C., more preferably in the range of from 40-80° C. andmost preferably, in the range of 50-70° C.

This temperature is maintained for at least one hour, preferably atleast two hours, more preferably at least three hours and mostpreferably at least four hours.

In a further preferred embodiment, after reacting the compound offormula (II) with an azodicarboxylic acid dialkyl ester, the reactionsolution is supplemented with 5,5-dimethylcyclohexane-1,3-dione(dimedone) or hydrazines and methanol.

The reason for using dimedone or hydrazines is that during thedemethylation reaction an aminal is formed, which is hydrolized withmethanol to yield the secondary amine (N—H) andformaldehyde-dimethylacetal (or formaldehyde following hydrolysation).In order to remove formaldehyde from the reaction mixture, a compoundsuitable for capturing the same will enhance the purity of the reaction.Any other compound suitable of capturing formaldehyde may be used inaddition or in place of dimedone or a hydrazines.

Dimedone preferably is used in an amount of at least 2 Eq, for example2-3.5 Eq regarding the presumed amount of formaldehyde(-dimethylacetal). An example of a preferred amount is about 3.0. Eq.

Preferably, the reaction solution is maintained at a temperature in therange of room temperature (20° C.) to 100° C., preferably in the rangeof 30-80° C., more preferably in the range of 40-70° C. over a time of1-10 hours, preferably 2-5 hours after adding dimedone/hydrazines andmethanol. A most preferred temperature range is 50-65° C.

In a further preferred embodiment, following reacting the compound offormula (II) and optionally reacting with dimedone and methanol, an acidis added to the reaction solution. The reason for adding an acid is toprotonate the reaction product in order to bring it in the polar (water)phase. The remaining substances (for example DEAD or DIAD) are separatedinto the organic phase and, thus, removed.

In more detail, when the reaction of the compound of formula II withR¹OOC—N═N—COOR² is complete, an acid as mentioned above (for examplehydrochloric acid), water and an organic solvent is added. The organicsolvent is not restricted in its kind and is preferablymethylenehloride. Thus, two phases arise, wherein the organic phase (forexample methylenehloride) will incorporate the remaining amounts ofR¹OOC—N═N—COOR² (DIAD or DEAD, for example) and formaldehyde/dimedone.

The aqueous phase in turn receives the reaction product as ahydrochloride, and, thus, is separating it from the reaction mixture.

Basically, any conceivable type of acid may be used for this purpose,however, hydrochloric acid turned out to be most promising. Thehydrochloric acid preferably has a concentration of about 5% V/V.

In a preferred embodiment of the invention, the reaction solutionfurther comprises at least one antioxidant. It was found that theaddition an antioxidant can prevent the formation of oxidativeby-products. In the inventive method, oxidative by-products can beformed, depending on the reaction conditions. The removal of theseby-products might require additional purification steps. Especiallydifficult to remove are2,2′-bis(14-hydroxy-14-methyl-4.5-epoxyrnorphinane-6-one)-derivativeswhich can only be removed by tedious purification procedures. Inpreferred embodiments, the amount of antioxidants in the reactionmixture is 1 to 50 mol-%, 5 to 40 mol-% or 10 to 30 mol-%. The additionof antioxidants can thus significantly improve the purity of thereaction product and reduce the process steps and costs of the reaction.

Suitable antioxidants are ascorbic acid and its derivatives, citricacid, tartric acid, polyhydroxy butyric acid (PHB) esters, butylatedhydroxyanisol (BHA) and butylated hydroxytoluene (BHT), preferably2,6-di-tert-butyl-4-methylphenol. Further suitable antioxidants areselected from the group consisting of organic acids and carboxylicacids, acid salts of amino acids, sodium metabisulphite, malic acid,isoascorbic acid, sodium sulphite, sodium bisulphate, tocopherol, water-and fat-soluble derivatives of tocopherol, sulphites, bisulphites andhydrogen sulphites, 2,6-di-t-butyl-alpha-dimethylamino-p-cresol,t-butylhydroquinone, di-t-amylhydroquinone, di-t-butylhydroquinone,butylhydroxytoluene, pyrocatechol, pyrogallol, propyl/gallate, andnordihydroguaiaretic acid, phosphoric acids, sorbic and benzoic acids,esters and derivatives thereof.

Throughout this specification the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated element, integer or step, or group of elements, integers orsteps, but not the exclusion of any other element, integer or step, orgroup of elements, integers or steps.

All publications mentioned in this specification are herein incorporatedby reference. Any discussion of documents, materials, devices, articlesor the like which has been included in the present specification issolely for the purpose of providing a context for the present invention.

The present invention now is described in more detail by means ofFigures and Examples.

In the Figures, the following is shown:

FIG. 1 shows a reaction scheme showing one conventional way of thesynthesis of naltrexone base. The demethylation step fromacetyloxycodone to noroxycodone is done by means of conventional means(BrCN/H₂SO₄). The 14 OH-group is protected before the demethylation stepis performed.

FIG. 2 shows a further reaction scheme showing one conventional way ofthe synthesis of naltrexone base. The demethylation step fromacetyloxymorphone to noroxymorphone is done by means of conventionalmeans (BrCN/H₂SO₄). The 14 OH-group is protected before thedemethylation step is performed.

FIG. 3 shows a reaction scheme showing an example of the synthesis ofthe present invention. The demethylation step from acetyloxycodone tonoroxycodone is done by means of DEAD or DIAD. The 14 OH-group is notprotected before the demethylation step is performed.

FIG. 4 shows a reaction scheme showing a further example of thesynthesis of the present invention. The demethylation step fromacetyloxymorphone to noroxymorphone is done by means of DEAD or DIAD.The 14 OH-group the like is not protected before the demethylation stepis performed.

FIG. 5 shows a comparison of a way of synthesis according to aconventional approach (1^(st) synthesis) and according to one embodimentof the present invention (2^(nd) synthesis).

EXAMPLES

The following is an illustration of one way to carry out the invention.The Example is related to the demethylation of oxymorphone, however canalso be performed for any conceivable compound reflected by formula(II).

N-Demethylation with an Azodicarboxylate:

INPUT: Content Amount in g Name of material mmol in % 50.0 Oxymorphone154.8 93.3 w/w 233.0 Dimethyl formamide pure 62.6Diisopropylazodicarboxylat (DIAD) 309.6 65.15,5-Dimethylcyclohexane-1,3-dione 464.3 (Dimedone) 19.8 Methanol pure618.8 610.0 Dichlormethane 27.4 Hydrochloride acid approximately 32%240.5 32 technical 450.0 Deionised water 26.2 Ammonia solutionapproximately 25%, 384.6 25 pure 120.0 Acetone 1664.1 Sum — — OUTPUT:Content Amount in g Name of material mol in % 1 42.6 Noroxymorphone130.3 87.9 287.31 PROCESS: 1 50.0 g Oxymorphone are solved at roomtemperature in 233.0 g dimethylformamide at room temperature andsupplemented with 62.6 g diisopropylazodicarboxylate. The solution isheated to 55° C. and a yellow to red mixture is formed. The solution isstirred for 4 hours at this temperature. 2 Progress of the reaction iscontrolled by HPLC for example. 3 To the reaction mixture 65.1 gdimedone and 19.8 g methanol are added starting at 55° C. 4 The mixtureis kept at a temperature of 60° C. whereas viscosity drops. The reactionmixture is stirred for 4 hours at a temperature of 60° C. 5 The reactionmixture is kept at a temperature of 20° C. and is supplemented with460.0 g dichlormethane, 200.0 g deionised water and 27.4 g hydrochloricacid 32% and is stirred for at least 5 min. Two clear phases are formed:a redish organic and a yellow aqueous phase. 6 The aqueous phase isseparated. 7 The aqueous phase is washed with 150.0 g dichlormethane.The phases are separated. 8 To the aqueous phase 26.2 g aqueuos ammoniasolution (25% w/w) are added at 20° C. under stirring. A suspension isformed.

The further steps in the procedure comprise purification as used inchemistry. The steps described illustrate a possible way.

PURIFICATION: 9 The suspension is brought to a temperature of 15° C. andstirred for at least two hours. 10 The suspension is vacuum-filtered,dried and the residue is slurried with 250.0 g water at a temperature of20° C. 11 The suspension is vacuum-filtered and dried well byaspiration. 12 The filter residue is slurried with 100.0 g acetone at atemperature of 20° C., vacuum- filtered and is dried well by aspiration.13 The filter residue is again washed with  20.0 g acetone and welldried by aspiration. 14 The product is dried in a vacuum drying oven at60° C. 15 42.6 g product is yielded as a fawn solid.

As it can be derived from table 1, showing the influence of the solventsand the amount of DIAD on the yield of demethylated products,dimethylacetamide, dimethylformamide and mixtures ofdimethylformamide/toluene brought about the highest reaction yield.Further, the amount of DIAD used preferably was in the range of 1.5 to3.0 eq.

TABLE 1 Noroxycodone: Examining the influence of the solvent and eq DIADat 50° C. Solvent conc. of eq HPLC Solvent System educt DIAD after EductProduct Toluene 10% 1.6 2.5 h 82.4%  11.1% 20 h 19.7%  61.4% Toluene 10%2.5 2.5 h 72.2%  26.2% 20 h 1.7% 66.7% Toluene 10% 4.1 2.5 h 57.3% 38.3% 20 h 0.00%  79.8% Acetone 10% 1.6 2.5 h 72.1%  25.0% 20 h 11.0% 76.2% Acetone 10% 2.5 2.5 h 52.0%  42.3% 20 h 0.00%  86.0% Acetone 10%4.1 2.5 h 36.0%  56.1% 20 h 1.2% 86.3% Methanol 10% 1.6 2.5 h 47.1% 20.3% 20 h 37.3%  8.5% Methanol 10% 2.5 2.5 h 3.0% 41.6% 20 h 1.5% 18.8%Methanol 10% 4.1 2.5 h 2.5% 50.4% 20 h 1.4% 20.0% Ethanol 10% 1.6 2.5 h36.3%  38.5% 20 h 2.1% 31.8% Ethanol 10% 2.5 2.5 h 13.4%  56.0% 20 h0.00%  26.0% Ethanol 10% 4.1 2.5 h 8.3% 63.2% MTBE 10% 3.0 16 h 26.5% 69.3% DMF 17% 3.0 16 h 1.0% 86.3% 42 h 1.6% 84.5% DMAc 17% 3.0 16 h 0.7%91.0% 42 h 0.5% 92.5% ACN 17% 3.0 16 h 1.0% 80.0% EE 17% 3.0 16 h 3.5%81.0% Toluene 33% 2.0 16 h 4.0% 69.0% Toluene  7% 2.0 16 h 28.0%  62.0%Toluene 33% 4.0 16 h 1.0% 71.0% 42 h 1.0% 58.0% Toluene  7% 4.0 16 h7.0% 79.0% Toluene 20% 3.0 5 d 20° C. 2.0% 83.0% DMF 17% 3.0 17 h 1.0%79.0% DMF 10% 3.0 17 h 1.0% 91.0% DMF 28% 3.0 17 h 1.0% 85.0% DMF 17%2.0 17 h 1.0% 89.0% 1DMF 17% 1.5 17 h 1.0% 89.0% DMF/Toluene 6/1 (w/w)15% 3.0 17 h 1.0% 88.0% DMF/Toluene 1/1 (w/w) 15% 3.0 17 h 1.0% 86.0%DMF/Toluene 1/6 (w/w) 15% 3.0 17 h 2.0% 85.0% DMF/Toluene 1/1 (w/w) 15%1.5 16 h 0.0% 89.0% DMF/Toluene 1/1 (w/w) 15% 2.0 16 h 1.0% 89.0%DMF/Toluene 1/6 (w/w) 15% 1.5 16 h 11.0%  76.0% DMF/Toluene 1/6 (w/w)15% 2.0 16 h 3.0% 83.0% DMF/Toluene 1/1 (w/w)  7% 1.5 16 h 4.0% 90.0%DMF/Toluene 1/1 (w/w)  7% 2.0 16 h 0.0% 92.0% DMF/Toluene 1/6 (w/w)  7%1.5 16 h 23.0%  70.0% DMF/Toluene 1/6 (w/w)  7% 2.0 16 h 12.0%  81.0%DMF 15% 1.0 16 h 9.0% 83.0% Toluene dry  7% 2.0 20 h 5.0% 69.0%Toluene/water 95/5 (w/w)  7% 2.0 20 h 11.0%  62.0% DMF/water 98/2 (w/w)14% 2.0 16 h 0.7% 79.7% Data indicated as analysed by HLPC.

TABLE 2 Noroxycodone: Examining the influence of the solvent and eq DEADat 50° C. conc. of eq HPLC Solvent educt DEAD after Educt ProductToluene 10% 2.0 16 h 10.0% 64.0% Data indicated as analysed by HLPC.

TABLE 3 Noroxymorphone: Examining the influence of the solvent and eqDIAD at 50° C. conc. of eq HPLC Solvent educt DIAD after Educt ProductDMF 13% 2.0 17 h 4.6% 89.1% DMF 13% 2.0 16 h 1.5% 73.2% Data indicatedas analysed by HLPC.

As shown in the table 4 below 2,2′-bisnoroxymorphone is formed as anunwanted side-product in the transformation of oxymorphone tonoroxymorphone following the method described above. The amount of theby-products depends on the reaction conditions. In the presence of 25mol-% of butylated hydroxytoluene (BHT), the formation of by-products,especially of 2,2′-bisnoroxymorphone, which is hard to remove otherwise,can be suppressed.

Addition Reaction Noroxymorphone 2,2′-Bisnoroxymorphone of BHT time(reaction product) (impurity) Yes  4 h 92.6%*⁾ 0.0%*⁾ No  4 h 90.9% 0.7%Yes 16 h 92.7% 0.0% No 16 h 89.7% 1.5% *⁾= area-% with HPLC

1. A method of producing a compound of formula (I)

or a salt thereof, comprising: reacting a compound of formula (II)

with an azodicarboxylic acid dialkyl ester of general formulaR¹OOC—N═N—COOR² in a suitable solvent, and at least one antioxidant,wherein X is selected from H, alkyl, silyl or acetyl; and R¹ and R² areindependently selected from a linear or branched substituted orunsubstituted alkyl, and wherein the bond between atoms 7 and 8 issingle or a double bond.
 2. The method according to claim 1, wherein thesolvent is an aprotic dipolar solvent.
 3. The method according to claim1, wherein the reaction is performed at a temperature in the range offrom 20° C. to 100° C.
 4. The method of claim 3, wherein the temperatureis maintained for at least one hour.
 5. The method of claim 1, whereinafter reacting the compound of formula (II) with an azodicarboxylic aciddialkyl ester, the reaction solution is supplemented with5,5-dimethylcyclohexane-1,3-dione (dimedone) and methanol or hydrazinesand methanol.
 6. The method of claim 5, wherein the reaction solution ismaintained at a temperature in the range of from 20° C. to 100° C. overa time of 1-10 hours after adding dimedone and methanol.
 7. The methodaccording to claim 5, wherein following reacting the compound of formula(II) and optionally reacting with dimedone/hydrazines and methanol, anacid is added to the reaction solution.
 8. The method of claim 7,wherein the acid is a hydrochloric acid.
 9. The method according toclaim 8, wherein the hydrochloric acid has a concentration of about 5%V/V.
 10. The method according to claim 1, wherein the antioxidant isselected from the group consisting of ascorbic acid and its derivatives,citric acid, tartric acid, polyhydroxy butyric acid (PHB) esters,butylated hydroxyanisol (BHA) and butylated hydroxytoluene (BHT). 11.The method according to claim 1, wherein R¹ and/or R² are independentlyselected from a linear or branched, substituted or unsubstituted, C₁-C₆alkyl.
 12. The method according to claim 11, wherein R¹ and/or R² areindependently selected from methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, tert-butyl, pentyl, and hexyl.
 13. The methodaccording to claim 12, wherein R¹ and/or R² are independently selectedfrom isopropyl and ethyl.
 14. The method according to claim 13, whereinR¹ and/or R² are identical.
 15. The method according to claim 2, whereinthe aprotic dipolar solvent is selected from the group consisting ofmethanol, ethanol, acetone, toluene, dimethylformamide,N,N-dimethylacetamide, acetonitrile, acetic acid ethylester andmethyl-tert-butylether.
 16. The method of claim 15, wherein the solventis dimethylformamide.
 17. The method according to claim 3, wherein thereaction is performed at a temperature in the range of from 30-90° C.18. The method according to claim 3, wherein the reaction is performedat a temperature in the range of from 40-80° C.
 19. The method accordingto claim 3, wherein the reaction is performed at a temperature in therange of from 50-70° C.
 20. The method of claim 4, wherein thetemperature is maintained for at least two hours.
 21. The method ofclaim 4, wherein the temperature is maintained for at least three hours.22. The method of claim 4, wherein the temperature is maintained for atleast four hours.
 23. The method of claim 6, wherein the reactionsolution is maintained at a temperature in the range of from 20° C. to100° C. for a period of time of from 2 to 5 hours after adding dimedoneand methanol.
 24. The method of claim 5, wherein the reaction solutionis maintained at a temperature in the range of from 30 to 80° C. for aperiod of time of from 1 to 10 hours after adding dimedone and methanol.25. The method of claim 24, wherein the reaction solution is maintainedat a temperature in the range of from 30 to 80° C. for a period of timeof from 2 to 5 hours after adding dimedone and methanol.
 26. The methodof claim 5, wherein the reaction solution is maintained at a temperaturein the range of from 40 to 70° C. for a period of time of from 1 to 10hours after adding dimedone and methanol.
 27. The method of claim 26,wherein the reaction solution is maintained at a temperature in therange of from 40 to 70° C. for a period of time of from 2 to 5 hoursafter adding dimedone and methanol.
 28. The method according to claim10, wherein the antioxidant is 2,6-di-tert-butyl-4-methylphenol.